Chronic inflammations constitute an increasing medical problem area of high socio-economic significance. This includes in particular the following groups of illnesses: autoimmune diseases and diseases from the area of rheumatic diseases (manifestations among others on the skin, lungs, kidneys, vascular system, nervous system, connective tissue, locomotor system, endocrine system), immediate-type allergic reactions and asthma, chronic obstructive lung diseases (COPD), arteriosclerosis, psoriasis and contact eczema and chronic rejection reactions after organ and bone marrow transplants. Many of these diseases are showing a rising prevalence in the last decades not only in industrial nations, but sometimes around the world. For example, in Europe, North America, Japan and Australia more than 20% of the population suffers from allergic diseases and asthma. Chronic obstructive lung diseases are currently the fifth most frequent cause of death throughout the world and according to calculations of the WHO they will represent the third most frequent cause of death in the year 2020. Arteriosclerosis with the secondary diseases of cardiac infarction, stroke and peripheral arterial disease leads the world in morbidity and mortality statistics. Together with neurodermatitis, psoriasis and contact eczema are in general the most frequent chronic inflammatory diseases of the skin.
Asthma is a common chronic inflammatory disease of the airways, comprising variable airway obstruction, mucus hyper-secretion, airway inflammation and increased airway hyper-responsiveness. Dysregulation of innate and adaptive immune responses is considered to play a central role in the development of the disease. A high degree of inter-individual heterogeneity has been identified among different patient populations leading to the definition of several clinical phenotypes and pathophysiological endotypes.1 The best studied pathophysiological asthma condition is the T-helper (TH)-2 driven (allergic) response2,3, which is also termed the “TH2 molecular endotype”4,5.
Approximately half of patients with asthma, regardless of disease severity, exhibit this TH2 endotype, which is characterized by a predominant activation of TH2 cells producing cytokines such as IL-4, IL-5, and IL-13. The expression and production of all these TH2 cytokines is critically controlled by the zinc finger transcription factor GATA-3, which is essential for TH2 cell differentiation and activation and considered the master transcription factor of the type 2 (TH2) pathway of immune activation6. GATA-3 is primarily responsible for the differentiation of naïve CD4+ T cells to TH2 cells. In the process, the TH2 cell differentiation is primarily controlled by two signal transmission pathways, the T cell receptor (TZR) and the IL-4 receptor pathway: Signals forwarded from TZR activate the TH2 cell-specific transcription factors cMaf and GATA-3 as well as also the transcription factors NFAT and AP-1. The activation of the IL-4 receptor results in the binding of STAT6 on the cytoplasmic domain of the IL-4 receptor, where it is phosphorylated by Jak1 and Jak3 kinases. The phosphorylation for its part results in the dimerization and translocation of STAT6 to the nucleus, where STAT6 activates the transcription of GATA-3 and other genes. GATA-3 is a zinc finger transcription factor which is expressed exclusively in mature TH2 cells, not in TH1 cells. GATA-3 overexpression has been observed in bronchoalveolar lavage samples and lung biopsies from patients with severe asthma despite optimal therapy according to the GINA guidelines7. This immune network is therefore a promising therapeutic target. In addition to the already approved anti-IgE monoclonal antibodies, several new therapeutics targeting individual components downstream of the transcription factor GATA-3 are in development8.
An alternative approach directly targets the strategic transcription factor GATA-3 to interfere with all down-stream molecules/cytokines simultaneously. GATA-3 expression has been analyzed in order to determine the molecular phenotype of patients suffering from chronic inflammatory diseases and to stratify patients in “TH2 high” and “TH2 low” subgroups, and it was suggested to treat “TH2 high” patients with GATA-3 specific inactivators (WO 2014/040891). Since GATA-3 is only expressed intracellularly, nucleic acid-based inactivators of GATA-3, such as GATA-3-specific DNAzymes, with in vivo cell-penetrating capabilities have been developed (WO 2005/033314).
In chronic inflammatory disorders, such as in allergic asthma, the problem of identifying an appropriate treatment scheme is more complex though. It is known that in allergic reactions, the number of eosinophils is increased, resulting in eosinophilia in certain patients. Eosinophils, however, are known to express GATA-3 as well (Zon et al., Blood 81 (1993) 3234-3241), since the expression of GATA-3 is not restricted to T cells, and expression of GATA-3 was also able to be confirmed in basophils, mast cells and epithelial cells. GATA-3 plays a central role in the immunopathogenesis of chronic inflammatory diseases, in particular of allergic asthma. It was shown that an acute sensitization and challenge with an allergen results in a high degree of eosinophil accumulation in the airways with minimal recruitment of lymphocytes (Paul Justice et al., Am J Physiol Lung Cell Mol Physiol 282 (2002) L302-L309), and that allergen challenge induces expression of GATA-3 and GATA-3-responsive genes in pulmonary eosinophils. In summary, it was postulated that eosinophils might provide positive feedback for the inflammatory response. In contrast, it had been shown that in chronic allergic airway inflammation, such as in allergic asthma, 60-90% of the GATA-3-positive cells in human lung tissue were CD3-positive T cells, and only less than 15% of the cells were identified as eosinophils (Nakamura et al., J Allergy Clin Immunol 103 (1999) 215-222). It was therefore concluded that in human asthma, eosinophil expression of GATA-3-responsive genes was likely not the primary source of proinflammatory cytokines leading to airway inflammation, but might just provide a redundant source of TH2 cytokines to support the chronic inflammatory process (Paul Justice et al., loc. cit.).
Thus, while GATA-3 in TH2 cells appears to be an attractive target for therapeutic intervention in the case of allergic disorders such as allergic asthma, it was completely unknown, what impact, if any, the simultaneous presence of eosinophils, which express GATA-3 as well, might have on the success of such a treatment approach. It was furthermore not predictable at all, whether it would be possible to identify certain patient populations that particularly benefit from such an approach.
Thus, there is still a large unmet need to develop novel and efficient therapies for patients with allergic asthma. The solution presented in this application, which is based on the identification of certain patient populations that particularly benefit from the administration of certain GATA-3 inhibitors, was not knows so far and could not have been expected by anyone of ordinary skill in the art.